S4-01-02

S68

Symposia S4-01: Diagnosis & Clinical Course (Biomarkers)

PL-04-03

IMAGING THE DEMENTIAS-DIAGNOSTIC PATTERNS

Bruce Miller, UCSF School of Medicine, San Francisco, CA, USA. Contact e-mail: [email protected] Abstract not available. WEDNESDAY, JULY 19, 2006 SYMPOSIA S4-01 DIAGNOSIS & CLINICAL COURSE (BIOMARKERS) S4-01-01

IDENTIFICATION OF SUBGROUPS OF ALZHEIMER DISEASE

Khalid Iqbal, Sabiha Khatoon, Hidenaga Yamamori, Inge Grundke-Iqbal, NY State Institute for Basic Research in Development Disabilities, Staten Island, NY, USA. Contact e-mail: [email protected] Background: Alzheimer disease (AD) is multifactorial and heterogenous. In less than 1% of cases, the disease co-segregates with certain mutations in ␤-amyloid precursor protein, presenilin-1, or presenilin-2 genes. The cause(s) of the disease in the remaining more than 99% is not understood. The two major challenges in developing neuroprotective therapeutic drugs for AD are identification of various subgroups of this multifactorial disease, and of the outcome measures with which efficacy of a test drug for each disease subgroup can be monitored. Objective(s): We postulate that more than one disease mechanism yields Alzheimer’s histopathology, and that subgroups of the disease might be identified by the cerebrospinal fluid (CSF) levels of proteins associated with senile (neuritic) plaques and neurofibrillary tangles, and that determination of the levels of phosphorylation of CSF tau at specific sites might lead to identification of the involvement of different specific signaling pathways in different subgroups of AD. Methods: We immunoassay levels of tau, ubiquitin, and A␤1-42, and of phosphorylation at different specific sites in retrospectively collected CSF samples of clinically diagnosed AD patients and non-AD subjects, and subject all cases to latent profile analysis based on the levels of these markers. Results: AD cases subdivided into at least five subgroups based on the levels of tau, A␤1-42, and ubiquitin. Each subgroup presented a different clinical profile. Conclusions: There are at least five subgroups of AD which can be identified based on the CSF levels of tau, A␤1-42, and ubiquitin. Different AD subgroups might involve different signaling pathways. We have developed ultrasensitive bienzyme-substrate-recycle ELISAs to determine the levels of different phosphotaus in CSF. With these assays, we will determine the levels of phosphorylation of tau at different specific sites to identify the possible involvement of different signaling pathways in AD. The identification of different subgroups of AD by CSF molecular markers will not only help determine the specific efficacy of a therapeutic drug towards each subgroup, but also these markers can serve as outcome measures for the drug. (Supported in part by the New York State Office of Mental Retardation and Developmental Disabilities and NIH Grant AG019158.). S4-01-02

P-TAU AS A BIOMARKER FOR EARLY DIAGNOSIS, CLASSIFICATION AND NEUROPATHOLOGY IN AD

Katharina Buerger1, Stefan J. Teipel1, Ray Zinkowski2, Tuula Pirttila¨3, Irina Alafuzoff4, Kaj Blennow5, Harald Hampel1, 1Alzheimer Memorial Center, University of Munich, Munich, Germany; 2Applied NeuroSolutions Inc., Vernon Hills, IL, USA; 3Dept. of Neuroscience and Neurology, Kuopio University Hospital, University of Kuopio, Finland; 4 Dept. of Pathology, Kuopio University Hospital, University of Kuopio, Finland; 5Dept. of Clinical Neuroscience, Sahlgren’s University Hospital, University of Go¨teborg, Mo¨lndal, Sweden. Contact e-mail: [email protected]

Objectives: Abnormally phosphorylated tau protein (p-tau) in cerebrospinal fluid (CSF) was studied as a potential biomarker of AD. Methods: Recently, immunoassays have been developed detecting specific phosphorylation epitopes of tau protein in the CSF. In a memory-clinic based design, patients with AD, other dementia disorders, and mild cognitive impairment (MCI), and neurological and healthy controls were included. Results: CSF levels of tau protein phosphorylated at threonine 231 (P-tau231) were highly increased in AD compared to healthy controls and other neurological disorders and further differentiated AD from its most relevant differential diagnoses including fronto-temporal dementia and major depression. In Creutzfeldt-Jakob disease, we showed a dissociation between P-tau and total tau. In AD, CSF P-tau231 declined with disease progression, correlating with cognitive performance at baseline. MCI patients showed elevated P-tau231 levels at baseline, correlating with rate of cognitive decline compared to healthy controls. In a comparative study using different P-tau epitopes associated with AD, P-tau reached specificity levels ⬎ 75% between AD and the combined non-AD group when sensitivity was set at 85%. A comparative study in MCI patients showed that different P-tau epitopes predict the rate of cognitive deterioration. A combination of different P-tau epitopes did not improve diagnostic or predictive accuracy. The apolipoprotein E genotype should be considered when P-tau is further evaluated as a biomarker of incipient AD in MCI subjects. Significant correlations were found between CSF P-tau231 and scores of neurofibrillary tangles and neuritic plaques in AD brains. CSF P-tau231 was also correlated to cortical load of hyperphosphorylated tau and to P-tau231 levels in brain homogenates suggesting that CSF P-tau231 likely reflects neurofibrillary pathology in the AD brain. Conclusions: Cumulative data indicates that quantification of CSF P-tau improves early detection, differential diagnosis and tracking of disease progression during the pre-dementia and clinical stages of AD. Moreover, it correlates to neurofibrillary pathology in the brain. The NIA biological markers working group recommends P-tau as a feasible, core biomarker candidate for large-scale validation studies, as well as clinical drug studies. S4-01-03

BETA-SECRETASE (BACE1) AS A PREDICTOR OF RISK IN ALZHEIMER DISEASE: HIGH LEVELS OF BACE1 IN CEREBROSPINAL FLUID OF MILD COGNITIVE IMPAIRMENT

Yong Shen1, Michael Ewers2, Stefan Teipel3, Katharina Bu¨ger4, Martin Citron5, Anders Wallin6, Kaj Blennow6, Todd Hager7, Jimin Wang8, Harald Hampel4, Jason Zhong1, 1Haldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, Sun City, AZ, USA; 2Ludwig-Maximilian University, Munich, Germany; 3 Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany; 4Department of Psychiatry, Ludwig-Maximilian University, Munich, Germany; 5Department of Neuroscience, Amgen Inc., Thousand Oaks, CA, USA; 6Department of Clinical Neuroscience, University of Go¨teborg, Mo¨ndal, Sweden; 7BioSource, Inc, Camarillo, CA, USA; 8 BioSource, Inc., Camarillo, CA, USA. Contact e-mail: [email protected] Background and Objective: Recently, we and others have discovered elevated ␤-secretase (BACE1) activity in brains of patients with sporadic Alzheimer’s disease (AD) compared to healthy control (HC) individuals. Now we are particularly interested in whether BACE1 could be identified in the cerebral spinal fluid (CSF) of patients with mild cognitive impairment (MCI), a population at high risk for AD. The possible presence of BACE1 in the CSF of AD and MCI has so far gone unreported. Methods: We evaluated the cerebrospinal fluid (CSF) BACE1 levels, enzymatic activities as well as total A␤ level from 80 sporadic AD patients, 59 MCI patients, and 69 healthy controls (HC) recruited from two independent research centers. Results: We found significant increases in both CSF BACE1 level and activity (p⬍ 0.001) in MCI compared to AD and HC. Elevated total A␤ level (p⬍0.001) in CSF of MCI patients was also found compared to AD patients and HC. CSF BACE1 activity was significantly correlated with BACE1 protein level (r⫽0.166, p⬍0.05). CSF A␤ level